EP1341764A1 - Composes bisaryl azotes a substitution ortho servant d'inhibiteurs de canaux de potassium - Google Patents

Composes bisaryl azotes a substitution ortho servant d'inhibiteurs de canaux de potassium

Info

Publication number
EP1341764A1
EP1341764A1 EP01999558A EP01999558A EP1341764A1 EP 1341764 A1 EP1341764 A1 EP 1341764A1 EP 01999558 A EP01999558 A EP 01999558A EP 01999558 A EP01999558 A EP 01999558A EP 1341764 A1 EP1341764 A1 EP 1341764A1
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
alkyl
phenyl
hydrogen
alkoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP01999558A
Other languages
German (de)
English (en)
Other versions
EP1341764B1 (fr
Inventor
Stefan Peukert
Joachim Brendel
Horst Hemmerle
Heinz-Werner Kleemann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Aventis Deutschland GmbH
Original Assignee
Aventis Pharma Deutschland GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aventis Pharma Deutschland GmbH filed Critical Aventis Pharma Deutschland GmbH
Priority to SI200130385T priority Critical patent/SI1341764T1/xx
Publication of EP1341764A1 publication Critical patent/EP1341764A1/fr
Application granted granted Critical
Publication of EP1341764B1 publication Critical patent/EP1341764B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to ortho, ortho-substituted nitrogen-containing bisaryl compounds of the formula I,
  • A1, A2, A3, A4, A5, A6, A7 and A8 independently of one another nitrogen, CH or CR (5), where at least one of these groups is nitrogen and at least 4 of these groups are CH;
  • R (1) C (O) OR (9), SO 2 R (10), COR (11), C (O) NR (12) R (13) or C (S) NR (12) R (13) ;
  • R (9), R (10), R (11) and R (12) independently of one another C x H2 ⁇ -R (14); x is 0, 1, 2, 3 or 4, where x cannot be 0 when R (14) is OR (15) or S ⁇ 2Me; R (14) alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF3, C2F5, C3F7, CH2F, CHF2, OR (15), S ⁇ 2Me, phenyl, naphthyl, biphenylyl, furyl,
  • R (13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF3
  • R (2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF3
  • R (3) C y H 2y -R (16); y is 0, 1, 2, 3 or 4, where y cannot be 0 when R (16) is OR (17) or S ⁇ 2Me;
  • OR (17) S ⁇ 2Me, phenyl, naphthyl, furyl, thienyl or an N-containing
  • R (18) is hydrogen or C Z H2 Z -R (16), where R (16) is as defined above; z 0, 1, 2 or 3;
  • R (21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms
  • R (4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF3; or
  • R (3) and R (4) together form a chain of 4 or 5 methylene groups, one of which
  • Methylene group can be replaced by -O-, -S-, -NH-, -N (methyl) - or -N (benzyl) -; R (5) independently of one another F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2 .
  • COMe COMe
  • R (30) and R (31) independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms; or
  • R (30) and R (31) together are oxygen or a chain of 2 methylene groups and their pharmaceutically acceptable salts.
  • Preferred compounds of the formula I are those in which: A1, A2, A3, A4, A5, A6, A7 and A8 independently of one another are nitrogen, CH or CR (5), at least one of these
  • Groups are nitrogen and at least 4 of these groups are CH; R (1) C (0) OR (9), SO 2 R (10), COR (11) or C (O) NR (12) R (13) R (9), R (10), R (11 ) and R (12) independently of one another C x H2 ⁇ -R (14); x 0, 1, 2, 3 or 4; where x cannot be 0 when R (14) is OR (15); R (14) alkyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR (15), phenyl, naphthyl, biphenylyl,
  • COMe NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R (15) alkyl with 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl with 3,
  • R (13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF3;
  • R (2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF3;
  • R (3) C y H 2y -R (16); y is 0, 1, 2, 3 or 4, where y cannot be 0 when R (16) is OR (17) or S ⁇ 2Me;
  • Atoms where phenyl, naphthyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO 2 , CN, COOMe, CONH 2 , COMe,
  • R (17) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3, phenyl or 2-, 3- or 4-pyridyl, where phenyl or 2-, 3- or 4-pyridyl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO 2 , CN, COOMe, CONH 2 , COMe , NH 2 , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2,
  • R (20) hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, C V H2 V -CF3 or C w H2w _ phenyl, where the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2,
  • R (4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF3;
  • R (5) independently of one another F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe,
  • R (30) and R (31) independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms; or R (30) and R (31) are a chain of 2 methylene groups and their pharmaceutically acceptable salts.
  • A1, A2, A3, A4, A5, A6, A7 and A8 independently of one another are nitrogen, CH or CR (5), where at least one and at most two of these groups are nitrogen and at least 4 of these groups are CH; R (1) C (O) OR (9), SO 2 R (10), COR (11) or C (O) NR (12) R (13);
  • R (13) hydrogen
  • R (2) hydrogen or alkyl having 1, 2 or 3 carbon atoms
  • R (3) CHR (18) R (19);
  • R (18) is hydrogen or C Z H2 Z -R (16), where R (16) is as defined above; z 0, 1, 2 or 3;
  • R (20) hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, C V H2 V -CF3 or C W H2 - phenyl, where the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN,
  • COOMe CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, Dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; v 0, 1, 2 or 3; w is 0, 1, 2 or 3; R (21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;
  • R (4) is hydrogen or alkyl having 1 or 2 carbon atoms;
  • R (5) independently of one another F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;
  • R (30) and R (31) independently of one another are hydrogen or methyl; as well as their pharmaceutically acceptable salts.
  • A1, A2, A3, A4, A5, A6, A7 and A8 independently of one another are nitrogen, CH or CR (5), where at least one and at most two of these groups are nitrogen and at least 4 of these groups are CH; R (1) C (O) OR (9), SO 2 R (10), COR (11) or C (O) NR (12) R (13);
  • R (9), R (10), R (11) and R (12) independently of one another C x H2 ⁇ -R (14); x 0, 1, 2, 3 or 4;
  • R (14) alkyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, phenyl, naphthyl, biphenylyl, furyl,
  • R (2) is hydrogen or methyl
  • R (3) C y H2 y -R (16); y 0, 1, 2, 3 or 4; where y cannot be 0 when R (16) is OR (17); R (16) alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5, 6, 7, 8, 9,
  • substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO 2 , CN, COOMe, CONH 2 , COMe, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
  • R (17) hydrogen, alkyl with 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, CF3, phenyl or 2-, 3- or 4-
  • pyridyl where phenyl or 2-, 3- or 4-pyridyl are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH 2 , COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-
  • R (4) is hydrogen or alkyl having 1 or 2 carbon atoms
  • R (5) independently of one another F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms
  • R (30) and R (31) independently of one another are hydrogen or methyl; as well as their pharmaceutically acceptable salts
  • R (9), R (10), R (11) and R (12) C x H 2x -R (14); x 0, 1, 2 or 3;
  • R (14) alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, phenyl or pyridyl, phenyl and pyridyl being unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, OH, alkyl with 1, 2 or
  • Atoms or alkoxy with 1 or 2 carbon atoms R (4) hydrogen; R (5) independently of one another F, Cl, CF3, CN, COOMe, CONH2 .
  • COMe NH2, OH, alkyl with 1, 2 or 3 C atoms or alkoxy with 1 or 2 C atoms;
  • R (30) and R (31) independently of one another are hydrogen or methyl; as well as their pharmaceutically acceptable salts.
  • R (1) C (0) OR (9) or COR (11); R (9) and R (11) independently of one another C x H2 ⁇ -R (14); x 0, 1, 2 or 3;
  • R (14) cycloalkyl with 5 or 6 carbon atoms or phenyl; where phenyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, OH, alkyl with 1, 2 or 3 carbon atoms or alkoxy with 1 or 2 carbon atoms
  • the compounds according to the invention are not yet known.
  • the compounds act on the so-called Kv1.5 potassium channel and inhibit a potassium stream called "ultra-rapidly activating delayed rectifier" in the human atrium.
  • the compounds are therefore particularly suitable as novel antiarrhythmic active ingredients, in particular for the treatment and prophylaxis of atrial Arrhythmias, e.g. atrial fibrillation (atrial fibrillation, AF) or atrial flutter (atrial flutter).
  • Atrial fibrillation and atrial flutter are the most common persistent cardiac arrhythmias.
  • AF affects approximately 1 million Americans annually and results in more than 80,000 strokes each year in the United States.
  • Class I and III antiarrhythmic drugs currently in use reduce the recurrence rate of AF, but are used only to a limited extent due to their potential proarrhythmic side effects. Therefore, there is a high medical need for the development of better drugs for the treatment of atrial arrhythmias (S. Nattel, Am. Heart J. 130, 1995, 1094-1106; "Newer developments in the management of atrial fibrillation").
  • Action potential is a recognized mechanism to stop arrhythmias or prevent them from developing (TJ Colatsky et al, Drug Dev. Res. 19, 1990, 129 - 140; "Potassium Channels as targets for antiarrhythmic drug action").
  • the length of the action potential is essentially determined by the extent of repolarizing
  • K + currents flowing out of the cell via various K + channels Particularly important is the so-called “delayed rectifier" l ⁇ , which consists of 3 different components: IK r , IK S and IK ur .
  • class III antiarrhythmics e.g. dofetilide, E4031 and d-sotalol
  • IK r the rapidly activating potassium channel
  • IK ur plays an important role in the human atrium, but not in the
  • Kv1.5 antiarrhythmics that act via a selective blockage of the IK ur current or Kv1.5 channel have not yet been available on the market.
  • WO 98 04 521 and WO 9937607 claim aminoindanes and aminotetrahydronaphtalins as potassium channel blockers which block the Kv1.5 channel. Structurally related aminochromanes are also claimed as Kv1.5 blockers in WO 0012077. In the application WO 9992891 thiazolidinones are claimed which also block the potassium channel.
  • the applications WO 98 18 475 and WO 98 18476 claim the use of various pyridazinones and phosphine oxides as antiarrhythmics, which are said to act by blocking the IK ur .
  • the same compounds were originally also described as immunosuppressants (WO 96 25 936). The ones mentioned in these Compounds described in applications are structurally completely different from the compounds according to the invention in this application. We do not know of any clinical data for any of the compounds claimed in the above applications.
  • the ortho, ortho-substituted nitrogen-containing bisaryl compounds described here are potent blockers of the human Kv1.5 channel. They can therefore be used as new antiarrhythmic drugs with a particularly advantageous safety profile.
  • the compounds are particularly suitable for the treatment of supraventricular arrhythmias, e.g. B. atrial fibrillation or atrial flutter.
  • connections can be used to terminate existing atrial fibrillation or flutter to regain the sinus rhythm (cardioversion).
  • the substances reduce the susceptibility to the development of new flicker events (maintenance of the sinus rhythm, prophylaxis).
  • the compounds according to the invention are not yet known.
  • Alkyl residues and alkylene residues can be straight-chain or branched. This also applies to the alkylene radicals of the formulas C x H2 ⁇ , CyH2y, C Z H2 Z , C V H2 and C w H2w Alkyl radicals and alkylene radicals can also be straight-chain or branched if they are substituted or are contained in other radicals, for. B. in an alkoxy radical or in a fluorinated alkyl radical.
  • alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3,3-dimethylbutyl, heptyl, octyl, Nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl.
  • the divalent residues derived from these residues e.g. B. methylene, 1, 1-ethylene, 1, 2-ethylene, 1, 1-propylene, 1, 2-propylene, 2,2-propylene, 1, 3-propylene, 1, 1-butylene, 1, 4- Butylene, 1, 5-pentylene, 2,2-dimethyl-1, 3-propylene, 1, 6-hexylene, etc. are examples of alkylene radicals.
  • Cycloalkyl radicals can also be branched.
  • Examples of cycloalkyl radicals with 3 to 11 carbon atoms are cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclopentyl, 2-methylcyclobutyl, 3-methylcyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, menthyl, cycloheptyl, cyclooctyl, cyclooctyl
  • N-containing heteroaromatics with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms are in particular 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl , 1-, 3-, 4- or 5-pyrazolyl, 1, 2,3-triazol-1-, -4- or 5-yl, 1, 2,4-triazoM-, -3- or -5-yl , 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1, 2,3-oxadiazol-4- or 5-yl, 1, 2,4-oxadiazole -3-or 5-yl, 1, 3,4-oxadiazol-2-yl or -5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1, 3,4 -Thiadiazol-2- or -5-yl, 1, 2,4-thiadiazol-3- or -5-yl, 1, 2,3-thiadiazol-4- or 5-yl,
  • N-containing heterocycles pyrrolyl, imidazolyl, quinolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl are particularly preferred.
  • Pyridyl represents both 2-, 3- and 4-pyridyl.
  • Thienyl represents both 2- and 3- thienyl.
  • Furyl stands for both 2- and 3-furyl.
  • Monosubstituted phenyl radicals can be substituted in the 2-, 3- or 4-position, disubstituted in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5 Position, trisubstituted in the 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5-position.
  • substituents can be the same or to be different.
  • R (3) and R (4) together represent a chain of 4 or 5 methylene groups, of which one methylene group can be replaced by -O-, -S-, -NH- etc., then these radicals form together with the nitrogen atom of formula I a 5 or 6-membered nitrogen heterocycle, such as Pyrrolidine, piperidine, morpholine, thiomorpholine etc.
  • the compounds of the formula I contain one or more acidic or basic groups or one or more basic heterocycles, the corresponding physiologically or toxicologically tolerable salts also belong to the invention, in particular the pharmaceutically usable salts.
  • the acidic groups, for. B. carry one or more COOH groups, for example as alkali metal salts, preferably sodium or potassium salts, or as alkaline earth metal salts, e.g. B. calcium or magnesium salts, or as ammonium salts, e.g. B. as salts with ammonia or organic amines or amino acids.
  • Compounds of formula I which one or more basic, i.e. H.
  • protonatable groups, groups or one or more basic heterocyclic rings can also be used in the form of their physiologically compatible acid addition salts with inorganic or organic acids, for example as hydrochlorides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleinates, fumarates, malates, gluconates etc.
  • the invention also includes, in addition to the salt forms described, internal salts, so-called betaines. Salts can be obtained from the compounds of the formula I by customary processes, for example by combining them with an acid or base in a solvent or dispersant or else by anion exchange from other salts.
  • the compounds of the formula I can be present in stereoisomeric forms. If the compounds of the formula I contain one or more centers of asymmetry, these can independently of one another Configuration or the R configuration.
  • the invention includes all possible stereoisomers, e.g. B. enantiomers or diastereomers, and mixtures of two or more stereoisomeric forms, e.g. B. enantiomers and / or diastereomers, in any ratio.
  • Enantiomers e.g. B. therefore belong to the invention in enantiomerically pure form, both as left-handed and right-handed antipodes, and also in the form of mixtures of the two enantiomers in different ratios or in the form of racemates.
  • the preparation of individual stereoisomers can be carried out by separating a mixture by customary methods or, for. B. done by stereoselective synthesis.
  • the present invention also encompasses all tautomeric forms of the compounds of the formula I.
  • the compounds of the formula I can be prepared by various chemical processes which also belong to the present invention. Some typical routes are outlined in the reaction sequences referred to below as schemes 1 to 4. A1 to A8 and the radicals R (1) to R (4), R (30) and R (31) are each defined as indicated above, unless stated otherwise below.
  • Bisaryls of the formula IV in which at least one of the ring atoms Ai to As is nitrogen can be isolated by palladium-catalyzed Suzuki coupling (which, for example, in the presence of Pd [(PPh 3 ) J4 as catalyst, sodium carbonate as base and 1, 2- Dimethoxyethane can be carried out as a solvent) of an aromatic halide of the formula III with an aromatic boronic acid of the formula II.
  • R (9) for an easily removable residue, such as. B. tert-butyl or benzyl compounds of formula V can be obtained, which can then be converted into compounds of formula I by reaction with reagents R (1) -X and / or R (2) -Y.
  • the reactions of the compounds of the formula V with compounds of the formula R (1) - X correspond to the known conversion of an amine into a carboxamide, sulfonamide, carbamate, urea or thiourea derivative.
  • the rest of X stands here for a suitable nucleofugic leaving group, such as F, Cl, Br, imidazole, O-succinimide etc.
  • R (1) is C (0) OR (9), i.e. carbamates, e.g. Compounds of the formula R (1) -X are used in which X represents chlorine or O-succinimide, that is to say chloroformates or succinimidocarbonates.
  • R (1) is COR (11)
  • carboxamides e.g. Compounds of the formula R (1) -X are used in which X represents chlorine, imidazole or acetoxy, that is to say carboxylic acid chlorides, carboxylic acid imidazolides or mixed anhydrides.
  • X represents chlorine, imidazole or acetoxy
  • the free acids of the formula R (1) -OH can also be used in the presence of suitable condensing agents such as carbodiimides or TFFH.
  • Bisaryls of the formula VIII in which at least one of the ring atoms A is nitrogen can be prepared by palladium-catalyzed Suzuki coupling of an aromatic bromide or iodide of the formula VII with an aromatic boronic acid of the formula II. Hydrolysis of the ester with LiOH gives the free acids of the formula IX which can be converted into the bisaryls of the formula IV by coupling with amines NHR (3) R (4). As described in Scheme 1, cleavage of the labile group R (9) gives compounds of the formula V which can be further converted into compounds of the formula I.
  • R (4) correspond to the known conversion of a carboxylic acid a carboxylic acid amide.
  • Numerous methods have been described in the literature for carrying out these reactions. They can be carried out particularly advantageously by activating the carboxylic acid, for example with dicyclohexylcarbodiimide (DCC) or N-ethyl-N'- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), optionally with the addition of hydroxybenzotriazole (HOBt) or dimethylaminopyridine (DMAP).
  • DCC dicyclohexylcarbodiimide
  • EDC N-ethyl-N'- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • HABt hydroxybenzotriazole
  • DMAP dimethylaminopyridine
  • reactive acid derivatives can also first be synthesized by known methods, for example acid chlorides by reacting the carboxylic acids of the formula IX or with
  • Acid imidazolides by reaction with carbonyldiimidazole, which are then subsequently, optionally with the addition of an auxiliary base, reacted with the amines of the formula HNR (3) R (4).
  • aromatic boronic acids of the formula II required in methods A and B can be synthesized from the aromatics or aromatic halides of the formula VI by ortholithiation or halogen-metal exchange, followed by reaction with trimethyl borate (or other triesters of boric acid) and subsequent acidic hydrolysis.
  • the halides of the formula VII used in method B can be synthesized according to regulations known from the literature or are readily obtainable from the known acids of the formula X by conventional esterification methods.
  • the aromatic ortho-haloamides of the formula III used in method A can be obtained according to scheme 4 from the esters of the formula VII after hydrolysis to the acids X by coupling with amines NHR (3) R (4).
  • the amide bond can be formed in the manner described above for the reaction of compounds of the formula IX to IV.
  • the compounds of the formula I according to the invention and their physiologically tolerable salts can be used on animals, preferably on mammals, and in particular on humans, as a medicament on their own, in mixtures with one another or in the form of pharmaceutical preparations.
  • the present invention also relates to the compounds of the formula I and their physiologically tolerable salts for use as medicaments, their use in the therapy and prophylaxis of the clinical pictures mentioned and their use for the manufacture of medicaments therefor and medicaments with K + channel blocking effect.
  • the present invention furthermore relates to pharmaceutical preparations which, as an active ingredient, contain an effective dose of at least one compound of the formula I and / or a physiologically tolerable salt thereof, in addition to customary, pharmaceutically perfect excipients and auxiliaries.
  • the pharmaceutical preparations normally contain 0.1 to 90 percent by weight of the compounds of the formula I and / or their physiologically tolerable salts.
  • the pharmaceutical preparations can be prepared in a manner known per se.
  • the compounds of the formula I and / or their physiologically tolerable salts together with one or more solid or liquid galenic carriers and / or auxiliaries and, if desired, in combination with other active pharmaceutical ingredients are brought into a suitable administration form or dosage form, which then as Medicines can be used in human medicine or veterinary medicine.
  • Medicaments containing compounds of the formula I according to the invention and / or their physiologically tolerable salts can be administered orally, parenterally, for.
  • B can be administered intravenously, rectally, by inhalation or topically, the preferred application depending on the individual case, e.g. B. the respective appearance of the disease to be treated is dependent.
  • auxiliaries which are suitable for the desired pharmaceutical formulation on the basis of his specialist knowledge.
  • active substance carriers for example antioxidants, dispersants, emulsifiers, defoamers, taste correctives, preservatives, solubilizers, agents for achieving a depot effect, buffer substances or dyes can be used.
  • the compounds of formula I can also be combined with other active pharmaceutical ingredients in order to achieve an advantageous therapeutic effect.
  • advantageous combinations with cardiovascular active substances are possible.
  • other antiarrhythmics such as class I, class II or class III antiarrhythmics, such as, for example, IK S or IK r channel blockers, for example dofetilide, or further blood pressure-lowering substances such as ACE inhibitors (for example enalapril, captopril, ramipril), Angiotensin antagonists, K + channel activators, and alpha and beta receptor blockers, but also sympathomimetic and adrenergic compounds, as well as Na + / H + exchange inhibitors, calcium channel antagonists, phosphodiesterase inhibitors and other positive inotropic substances, such as. B. digitalis glycosides, or diuretics.
  • the active compounds are mixed with the suitable additives, such as carriers, stabilizers or inert diluents, and brought into the suitable dosage forms by conventional methods, such as tablets, dragées, capsules, aqueous, alcoholic or oily solutions.
  • suitable additives such as carriers, stabilizers or inert diluents
  • inert carriers such as gum arabic, magnesia, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch, can be used.
  • the preparation can take place both as dry and as moist granules.
  • Vegetable or animal oils such as sunflower oil or cod liver oil, are suitable as oily carriers or as solvents.
  • a solvent for aqueous or alcoholic solutions such.
  • Other auxiliaries are e.g. B. polyethylene glycols and polypropylene glycols.
  • the active compounds are brought into solution, suspension or emulsion, if desired with the usual substances such as solubilizers, emulsifiers or other auxiliaries.
  • the compounds of formula I and their physiologically acceptable salts can also be lyophilized and the resulting lyophilizates z.
  • B. can be used for the production of injection or infusion preparations.
  • solvents such.
  • B. water, physiological saline or alcohols, e.g. As ethanol, propanol, glycerol, in addition, also sugar solutions such as glucose or mannitol solutions, or mixtures of the various mentioned Solvents.
  • Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for. B. solutions, suspensions or emulsions of the active compounds of the formula I or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as in particular ethanol or water, or a mixture of such solvents.
  • a pharmaceutically acceptable solvent such as in particular ethanol or water, or a mixture of such solvents.
  • the formulation can also contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers and a propellant.
  • Such a preparation usually contains the active ingredient in a concentration of approximately 0.1 to 10, in particular approximately 0.3 to 3 percent by weight.
  • the dosage of the active ingredient of formula I to be administered or the physiologically tolerable salts thereof depends on the individual case and, as usual, is to be adapted to the circumstances of the individual case for an optimal effect. So of course it depends on the frequency of administration and the potency and duration of action of the compounds used for therapy or prophylaxis, but also on the type and potency of the disease to be treated as well as the gender, age, weight and individual responsiveness of the person to be treated or Animal and whether it is being treated acutely or prophylactically.
  • the daily dose of a compound of the formula I when administered to a patient weighing approximately 75 kg is 0.001 mg / kg body weight to 100 mg / kg body weight, preferably 0.01 mg / kg body weight to 20 mg / kg body weight.
  • the dose can be administered in the form of a single dose or in several, e.g. B. two, three or four single doses. Especially in the treatment of acute cases of
  • Cardiac arrhythmias for example in an intensive care unit, can also be administered parenterally by injection or infusion, e.g. B. by an intravenous continuous infusion, be advantageous.
  • esters VII were synthesized according to regulations known from the literature, and some were prepared from the acids X by esterification using standard laboratory methods.
  • Succinimidyl carbonate (or optionally the corresponding chloroformate) was added and the mixture was stirred overnight. It is diluted with dichloromethane and with NaHC03 solution washed. The organic phase is dried, concentrated and, if necessary, purified by RP-HPLC.
  • Kv1.5 channels were expressed in Xenopus oocytes.
  • oocytes from Xenopus laevis were first isolated and defolliculated.
  • Kv1.5 coding RNA synthesized in vitro was then injected into these oocytes.
  • Kv1.5 currents were measured on the oocytes using the two-microelectrode voltage-clamp technique.
  • the Kv1.5 channels were usually activated with 500 ms voltage jumps to 0 mV and 40 mV.
  • the bath was flushed with a solution of the following composition: NaCl 96 mM, KCI 2 mM, CaCl2 1.8 mM, MgC_2 1 mM, HEPES 5 mM (titrated with NaOH to pH 7.4). These experiments were carried out at room temperature. The following were used for data collection and analysis: Geneclamp amplifiers (Axon Instruments, Foster City, USA) and MacLab D / A converter and software (ADInstruments, Castle Hill, Australia). The substances according to the invention were tested by adding them to the bath solution in different concentrations. The effects of the substances were calculated as a percentage inhibition of the Kv1.5 control current which was obtained when no substance was added to the solution. The data was then extrapolated using the Hill equation to determine the inhibitory concentrations IC50 for the respective substances.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Les composés de la formule générale (I) dans laquelle A1 à A8, R(1), R(2), R(3), R(4), R(30) et R(31) ont la signification donnée dans le descriptif, sont particulièrement adaptés à une utilisation en tant qu'agents antiarythmiques, notamment pour le traitement et la prophylaxie d'arythmies de l'oreillette par ex. de fibrillations auriculaires ou de flutter auriculaire.
EP01999558A 2000-12-07 2001-11-24 Composes bisaryl azotes a substitution ortho servant d'inhibiteurs de canaux de potassium Expired - Lifetime EP1341764B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
SI200130385T SI1341764T1 (en) 2000-12-07 2001-11-24 Ortho-substituted nitrogen-containing bisaryl compounds used as potassium channel inhibitors

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10060807 2000-12-07
DE10060807A DE10060807A1 (de) 2000-12-07 2000-12-07 Ortho, ortho-substituierte stickstoffhaltige Bisarylverbindungen, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament sowie sie enthaltende pharmazeutische Zubereitungen
PCT/EP2001/013680 WO2002046162A1 (fr) 2000-12-07 2001-11-24 Composes bisaryl azotes a substitution ortho servant d'inhibiteurs de canaux de potassium

Publications (2)

Publication Number Publication Date
EP1341764A1 true EP1341764A1 (fr) 2003-09-10
EP1341764B1 EP1341764B1 (fr) 2005-06-15

Family

ID=7666129

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01999558A Expired - Lifetime EP1341764B1 (fr) 2000-12-07 2001-11-24 Composes bisaryl azotes a substitution ortho servant d'inhibiteurs de canaux de potassium

Country Status (31)

Country Link
US (1) US6794377B2 (fr)
EP (1) EP1341764B1 (fr)
JP (1) JP4445198B2 (fr)
KR (1) KR100815070B1 (fr)
CN (1) CN1237052C (fr)
AR (1) AR033408A1 (fr)
AT (1) ATE297897T1 (fr)
AU (2) AU2189202A (fr)
BR (1) BR0116005A (fr)
CA (1) CA2436891C (fr)
CZ (1) CZ301923B6 (fr)
DE (2) DE10060807A1 (fr)
DK (1) DK1341764T3 (fr)
EE (1) EE05220B1 (fr)
ES (1) ES2242792T3 (fr)
HK (1) HK1066539A1 (fr)
HR (1) HRP20030448B1 (fr)
HU (1) HUP0302762A3 (fr)
IL (2) IL156312A0 (fr)
MX (1) MXPA03004966A (fr)
NO (1) NO325297B1 (fr)
NZ (1) NZ526294A (fr)
PL (1) PL207057B1 (fr)
PT (1) PT1341764E (fr)
RU (1) RU2275360C2 (fr)
SI (1) SI1341764T1 (fr)
SK (1) SK286056B6 (fr)
TW (1) TWI242005B (fr)
WO (1) WO2002046162A1 (fr)
YU (1) YU40203A (fr)
ZA (1) ZA200303931B (fr)

Families Citing this family (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0124939D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124931D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124941D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124933D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124938D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124934D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124936D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
US7125898B2 (en) * 2002-02-12 2006-10-24 Smithkline Beecham Corporation Nicotinamide derivatives useful as p38 inhibitors.
GB0217757D0 (en) 2002-07-31 2002-09-11 Glaxo Group Ltd Novel compounds
GB0308185D0 (en) * 2003-04-09 2003-05-14 Smithkline Beecham Corp Novel compounds
GB0315950D0 (en) 2003-06-11 2003-08-13 Xention Discovery Ltd Compounds
DE10341233A1 (de) * 2003-09-08 2005-03-24 Aventis Pharma Deutschland Gmbh Kombination von Phenylcarbonsäureamiden mit beta-Adrenozeptoren-Blockern und deren Verwendung zur Behandlung von Vorhofarrhythmien
US20050054673A1 (en) * 2003-09-08 2005-03-10 Aventis Pharma Deutschland Gmbh Combination of phenylcarboxylic acid amides with beta-adrenoreceptor blockers and their use for the treatment of atrial arrhythmias
GB0402143D0 (en) * 2004-01-30 2004-03-03 Smithkline Beecham Corp Novel compounds
GB0412986D0 (en) 2004-06-10 2004-07-14 Xention Discovery Ltd Compounds
US7569589B2 (en) 2004-07-29 2009-08-04 Merck & Co., Inc. Potassium channel inhibitors
US20080051416A1 (en) * 2004-10-05 2008-02-28 Smithkline Beecham Corporation Novel Compounds
JP2008522978A (ja) * 2004-12-07 2008-07-03 エナンタ ファーマシューティカルズ インコーポレイテッド ３，６−ビシクロライド
US7576212B2 (en) 2004-12-09 2009-08-18 Xention Limited Thieno[2,3-B] pyridines as potassium channel inhibitors
GB0512429D0 (en) * 2005-06-17 2005-07-27 Smithkline Beecham Corp Novel compound
WO2007015775A2 (fr) * 2005-07-22 2007-02-08 Merck & Co., Inc. Inhibiteurs des canaux potassiques
GB0525164D0 (en) 2005-12-09 2006-01-18 Xention Discovery Ltd Compounds
WO2007124849A2 (fr) * 2006-04-27 2007-11-08 Sanofi-Aventis Deutschland Gmbh Inhibiteurs du canal ionique task-1 et task-3
GB0815782D0 (en) 2008-08-29 2008-10-08 Xention Ltd Novel potassium channel blockers
GB0815781D0 (en) 2008-08-29 2008-10-08 Xention Ltd Novel potassium channel blockers
GB0815784D0 (en) 2008-08-29 2008-10-08 Xention Ltd Novel potassium channel blockers
EP2459541A1 (fr) 2009-07-30 2012-06-06 F. Hoffmann-La Roche AG Amides de dihydropyrimidone utilisés comme modulateurs p2x7
GB201105659D0 (en) 2011-04-01 2011-05-18 Xention Ltd Compounds
NO3175985T3 (fr) 2011-07-01 2018-04-28
WO2013112932A1 (fr) 2012-01-27 2013-08-01 Gilead Sciences, Inc. Thérapies de combinaison à l'aide de bloqueurs de canaux ioniques au sodium tardifs et de bloqueurs de canaux ioniques au potassium
WO2014183221A1 (fr) * 2013-05-17 2014-11-20 The Centre For Drug Research And Development Analogues de resvératrol et leurs utilisations thérapeutiques
US12084472B2 (en) 2015-12-18 2024-09-10 Ardelyx, Inc. Substituted 4-phenyl pyridine compounds as non-systemic TGR5 agonists
TWI773657B (zh) 2015-12-18 2022-08-11 美商亞德利克斯公司 作爲非全身ｔｇｒ５促效劑之經取代之4-苯基吡啶化合物
EP3558992A4 (fr) 2016-12-15 2020-12-02 ONO Pharmaceutical Co., Ltd. Activateur de canaux trek (canaux k+ associés à twik)
UA128288C2 (uk) 2018-03-08 2024-05-29 Інсайт Корпорейшн СПОЛУКИ АМІНОПІРАЗИНДІОЛУ ЯК ІНГІБІТОРИ PI3K-<font face="Symbol">g</font>
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4616002A (en) * 1984-11-09 1986-10-07 Ciba-Geigy Corporation Dihydro pyridine compounds, compositions and use
US5196537A (en) * 1991-03-21 1993-03-23 G. D. Searle & Co. 5-apylheteroarylalkyl-1,3,5-trisubstituted-1,2,4-triazole compounds for treatment of circulatory disorders
DE4430638A1 (de) * 1994-08-29 1996-03-07 Bayer Ag Verwendung von substituierten 4-Phenyl-6-amino-nicotinsäurederivaten als Arzneimittel
US5670504A (en) 1995-02-23 1997-09-23 Merck & Co. Inc. 2,6-diaryl pyridazinones with immunosuppressant activity
US6083986A (en) * 1996-07-26 2000-07-04 Icagen, Inc. Potassium channel inhibitors
US5935945A (en) 1996-10-31 1999-08-10 Merck & Co., Inc. Methods of treating or preventing cardiac arrhythmia
US5969017A (en) 1996-10-31 1999-10-19 Merck & Co., Inc. Methods of treating or preventing cardiac arrhythmia
US6333337B1 (en) * 1998-01-27 2001-12-25 Icagen, Inc. Potassium channel inhibitors
CA2334258A1 (fr) 1998-06-05 1999-12-09 Icagen, Inc. Inhibiteurs des canaux de potassium
EP1109544A4 (fr) * 1998-09-01 2004-10-27 Bristol Myers Squibb Co Inhibiteurs de canaux potassium et leur methode d'utilisation
DE19947457A1 (de) * 1999-10-02 2001-04-05 Aventis Pharma Gmbh 2'-Substituierte 1,1'-Biphenyl-2-carbonamide, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament sowie enthaltende pharmazeutische Zubereitungen
DE10059418A1 (de) * 2000-11-30 2002-06-20 Aventis Pharma Gmbh Ortho, meta-substituierte Bisarylverbindungen, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament sowie sie enthaltende pharmazeutische Zubereitungen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0246162A1 *

Also Published As

Publication number Publication date
CN1237052C (zh) 2006-01-18
TWI242005B (en) 2005-10-21
HRP20030448A2 (en) 2005-04-30
KR100815070B1 (ko) 2008-03-20
CA2436891C (fr) 2011-01-11
HUP0302762A2 (hu) 2003-11-28
HUP0302762A3 (en) 2010-03-29
CA2436891A1 (fr) 2002-06-13
JP2004515493A (ja) 2004-05-27
AU2002221892B2 (en) 2006-07-13
YU40203A (sh) 2006-05-25
ZA200303931B (en) 2004-03-24
CN1537102A (zh) 2004-10-13
JP4445198B2 (ja) 2010-04-07
NO20032488D0 (no) 2003-06-02
BR0116005A (pt) 2004-01-06
PL207057B1 (pl) 2010-10-29
HK1066539A1 (en) 2005-03-24
ATE297897T1 (de) 2005-07-15
EE05220B1 (et) 2009-10-15
CZ301923B6 (cs) 2010-07-28
PL365318A1 (en) 2004-12-27
KR20030081344A (ko) 2003-10-17
NZ526294A (en) 2005-04-29
DK1341764T3 (da) 2005-10-17
DE50106549D1 (de) 2005-07-21
CZ20031564A3 (cs) 2003-09-17
NO325297B1 (no) 2008-03-17
MXPA03004966A (es) 2003-09-25
WO2002046162A1 (fr) 2002-06-13
IL156312A0 (en) 2004-01-04
EE200300225A (et) 2003-08-15
AR033408A1 (es) 2003-12-17
EP1341764B1 (fr) 2005-06-15
SI1341764T1 (en) 2005-10-31
RU2275360C2 (ru) 2006-04-27
ES2242792T3 (es) 2005-11-16
SK6872003A3 (en) 2004-02-03
PT1341764E (pt) 2005-09-30
AU2189202A (en) 2002-06-18
US6794377B2 (en) 2004-09-21
SK286056B6 (sk) 2008-02-05
US20030060470A1 (en) 2003-03-27
HRP20030448B1 (en) 2006-06-30
NO20032488L (no) 2003-08-04
IL156312A (en) 2009-05-04
DE10060807A1 (de) 2002-06-20

Similar Documents

Publication Publication Date Title
EP1341764B1 (fr) Composes bisaryl azotes a substitution ortho servant d&#39;inhibiteurs de canaux de potassium
EP1339675B1 (fr) Composes bisaryle substitues en ortho et meta, leur procede de fabrication, leur utilisation comme medicaments, et preparations pharmaceutiques les renfermant
EP1349846B1 (fr) Amides d&#39;acides furane et thiophene carboxyliques aryles ayant un effet de blocage de canal de potassium
EP1385820B1 (fr) Amides d&#39;acide anthranilique, leur procede de production, leur utilisation en tant qu&#39;antiarythmisants et preparations pharmaceutiques les renfermant
EP1194403B1 (fr) Benzolcarbonamides substitues par indanyle, leur procede de production, leur utilisation comme medicament et compositions pharmaceutiques les contenant
EP1222163B1 (fr) 1,1&#39;-biphenyl-2-carbonamides 2&#39;-substitues, procede de fabrication, utilisation en tant que medicament, ainsi que preparations pharmaceutiques contenant ces composes
WO2002087568A1 (fr) Utilisation d&#39;amides d&#39;acide anthranilique en tant que medicaments servant au traitement d&#39;arythmies et preparations pharmaceutiques les renfermant
DE10312061A1 (de) Kombination von Phenylcarbonsäureamiden mit Blockern des IK-Kanals und deren Verwendung zur Behandlung von Vorhofarrhythmien
EP1670551A1 (fr) Combinaison d&#39;amides de l&#39;acide phenylcarboxylique avec des bloquants des recepteurs beta-adrenergiques et leur utilisation dans le traitement d&#39;arythmies atriales

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20030707

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

RIN1 Information on inventor provided before grant (corrected)

Inventor name: HEMMERLE, HORST

Inventor name: KLEEMANN, HEINZ-WERNER

Inventor name: BRENDEL, JOACHIM

Inventor name: PEUKERT, STEFAN

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAJ Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR1

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Free format text: NOT ENGLISH

Ref country code: CH

Ref legal event code: EP

REF Corresponds to:

Ref document number: 50106549

Country of ref document: DE

Date of ref document: 20050721

Kind code of ref document: P

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

Free format text: LANGUAGE OF EP DOCUMENT: GERMAN

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20050402555

Country of ref document: GR

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Effective date: 20050808

GBT Gb: translation of ep patent filed (gb section 77(6)(a)/1977)

Effective date: 20050912

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2242792

Country of ref document: ES

Kind code of ref document: T3

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20051130

REG Reference to a national code

Ref country code: CH

Ref legal event code: PFA

Owner name: SANOFI-AVENTIS DEUTSCHLAND GMBH

Free format text: AVENTIS PHARMA DEUTSCHLAND GMBH#BRUENINGSTRASSE 50#95929 FRANKFURT (DE) -TRANSFER TO- SANOFI-AVENTIS DEUTSCHLAND GMBH#BRUENINGSTRASSE 50#65929 FRANKFURT AM MAIN (DE)

Ref country code: SI

Ref legal event code: SP73

Owner name: SANOFI-AVENTIS DEUTSCHLAND GMBH; DE

Effective date: 20060109

ET Fr: translation filed
NLT1 Nl: modifications of names registered in virtue of documents presented to the patent office pursuant to art. 16 a, paragraph 1

Owner name: SANOFI-AVENTIS DEUTSCHLAND GMBH

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20060316

REG Reference to a national code

Ref country code: FR

Ref legal event code: CD

BECN Be: change of holder's name

Owner name: *SANOFI-AVENTIS DEUTSCHLAND G.M.B.H.

Effective date: 20050615

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20101110

Year of fee payment: 10

Ref country code: DK

Payment date: 20101110

Year of fee payment: 10

Ref country code: IE

Payment date: 20101110

Year of fee payment: 10

Ref country code: NL

Payment date: 20101110

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20110110

Year of fee payment: 10

Ref country code: DE

Payment date: 20101130

Year of fee payment: 10

Ref country code: CH

Payment date: 20101112

Year of fee payment: 10

Ref country code: FI

Payment date: 20101110

Year of fee payment: 10

Ref country code: PT

Payment date: 20101116

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20101124

Year of fee payment: 10

Ref country code: GR

Payment date: 20101014

Year of fee payment: 10

Ref country code: TR

Payment date: 20101102

Year of fee payment: 10

Ref country code: SE

Payment date: 20101111

Year of fee payment: 10

Ref country code: IT

Payment date: 20101113

Year of fee payment: 10

Ref country code: BE

Payment date: 20101117

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CY

Payment date: 20101111

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20101217

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20111118

Year of fee payment: 11

BERE Be: lapsed

Owner name: *SANOFI-AVENTIS DEUTSCHLAND G.M.B.H.

Effective date: 20111130

REG Reference to a national code

Ref country code: PT

Ref legal event code: MM4A

Free format text: LAPSE DUE TO NON-PAYMENT OF FEES

Effective date: 20120524

REG Reference to a national code

Ref country code: NL

Ref legal event code: V1

Effective date: 20120601

LTLA Lt: lapse of european patent or patent extension

Effective date: 20111124

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: GR

Ref legal event code: ML

Ref document number: 20050402555

Country of ref document: GR

Effective date: 20120605

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111130

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120601

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111130

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111130

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120605

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120524

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111124

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111124

REG Reference to a national code

Ref country code: SI

Ref legal event code: KO00

Effective date: 20120629

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111124

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111130

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111125

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111124

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 297897

Country of ref document: AT

Kind code of ref document: T

Effective date: 20111124

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111124

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111124

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20130603

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20121124

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111125

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20130731

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 50106549

Country of ref document: DE

Effective date: 20130601

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20111124

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130601

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121130

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121124